DE69620241T2 - GONADOTROPIN RELEASING HORMONE ANTAGONISTS - Google Patents

Abstract

There are disclosed compounds of formula (I) and pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related and other conditions in both men and women.

Description

BACKGROUND OF THE INVENTION

Gonadotropin-releasing hormone (GnRH), also called luteinizing hormone-releasing hormone (LHRH), is a decapeptide that plays a key role in human reproduction. The hormone is released by the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH, released by the pituitary gland, is primarily responsible for controlling gonadal steroid production in both sexes, with FSH controlling spermatogenesis in males and follicle development in females. GnRH agonists and antagonists have been shown to be effective for treating certain conditions that require inhibition of LH/FSH release. Specifically, GnRH-based therapies have been shown to be effective in the treatment of endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty, and severe gonadal steroid-dependent neoplasia, particularly carcinoma of the prostate, breast, and ovary. GnRH agonists and antagonists have also been used in various assisted reproduction techniques and have been studied as a potential contraceptive in both men and women. They also have potential use in the treatment of gonadotrophic pituitary adenomas, sleep disorders such as sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hyperplasia, hirsutism, as an adjunct to growth hormone therapy in children with growth hormone deficiency, and in murine lupus models. The compounds of the invention can also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g. MK-0677, for the treatment and prevention of disorders of calcium, phosphate and bone metabolism, in particular for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms, such as hot flashes during therapy with the GnRH antagonist.

In addition, a compound of the present invention may be administered together with a 5α-reductase-2 inhibitor such as finasteride or epristeride. a 5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane and 3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as described in WO 93/23420 and WO 95/11254, dual inhibitors of 5α-reductase 1 and 5α-reductase 2 such as B. 3-oxo-4-aza-17β-(2,5-trifluoromethylphenylcarbamoyl)-5α-androstane as disclosed in WO 95/07927, antiandrogens such as flutamide, casodex and cyproterone acetate, and alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.

Furthermore, a compound of the present invention can be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues to delay puberty in children with growth hormone deficiency, thereby allowing them to continue to gain height prior to fusion of the epiphyses and cessation of growth at puberty.

The current GnRH antagonists are GnRH-like decapeptides, which are generally administered intravenously or subcutaneously, presumably because of negligible oral activity. These have amino acid substitutions, usually at positions one, two, three, six and ten.

Nonpeptide GnRH antagonists offer the potential advantage of oral administration. Nonpeptide GnRH antagonists have been described in European Application 0 219 292 and by De, B. et al., J. Med. Chem., 32, 2036-2038 (1989), WO 95/28405, WO 95/29900 and EP 0679642, all from Takeda Chemical Industries, Ltd.

Substituted indoles known in the art include those described in the following patents and patent applications: U.S. Patent No. 5,030,640 discloses alpha-heterocyclic ethanolaminoalkyl indoles which are potent β-agonists. U.S. Patent No. 4,544,663 discloses indoleamine derivatives which are said to be useful as male antifertility agents. WO 90/05721 discloses alpha-aminoindole-3-acetic acids which are useful as antidiabetic, antiobesity and antiatherosclerotic agents. French Patent 2,181,559 discloses indole derivatives having sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenolytic activity. Belgian Patent 879381 discloses 3-aminoalkyl-1H-indole-5-thioamide and -carboxamide derivatives as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are nonpeptide antagonists of GnRH which can be used to treat a range of sex hormone-related conditions in men and women, methods for their preparation, and methods and pharmaceutical compositions containing these compounds for use in mammals.

Due to their activity as antagonists of the hormone GnRH, the compounds of the present invention are useful for treating a number of sex hormone-related conditions in both men and women. These conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as carcinoma of the prostate, breast and ovary, gonadotrophic pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertrophy. They are also useful as an adjunct to the treatment of growth hormone deficiency and short stature and for the treatment of murine lupus erythematosus. Furthermore, the compounds of the invention may be useful for in vitro fertilization and as a contraceptive. The compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens, and antiprogestogens for the treatment of endometriosis, fibroids and for contraception. They may also be useful in combination with testosterone or other androgens or antiprogestogens in men as a contraceptive. The compounds may also be used in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril, an angiotensin II receptor antagonist such as losartan, or a renin inhibitor for the treatment of uterine fibroids. In addition, the compounds of the invention can also be used in combination with bisphosphonates (bisphosphonic acids) and other agents for the treatment and prevention of disorders of calcium, phosphate and bone metabolism, in particular for the prevention of bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones, antiestrogens, antiprogestins and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms, such as hot flashes during therapy with the GnRH antagonist.

In addition, a compound of the present invention may be administered together with a 5α-reductase-2 inhibitor such as finasteride or epristeride, a 5α-reductase-1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane and 3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as described in WO 93/23420 and WO 95/11254, dual inhibitors of 5α-reductase 1 and 5α-reductase 2 such as 3-oxo-4-aza-17β-(2,5-trifluoromethylphenylcarbamoyl)-5α-androstane as disclosed in WO 95/07927, antiandrogens such as flutamide, casodex and cyproterone acetate and alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.

Furthermore, a compound of the present invention can be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues to delay puberty in children with growth hormone deficiency, thereby allowing them to continue to gain height prior to fusion of the epiphyses and cessation of growth at puberty.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula

where

A is C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₁-C₆ alkoxy or C₀-C₅ alkyl-S(O)nC₀-C₅ alkyl, C₀-C₅ alkyl-OC₀-C₅ alkyl, C₀-C₅ alkyl-NR₁₈-C₀-C₅ alkyl, where R₁₈ and the C₀-C₅ alkyl may be joined to form a ring,

or a single bond,

wherein the alkyl, alkenyl, alkoxy and alkynyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluorine, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy,

R&sub0; is hydrogen, C1-C6 alkyl, aryl, aralkyl,

wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen,

R₁ is

R&sub2; is hydrogen, C1 -C6 alkyl, aralkyl, aryl, alkyl-OR11 , C1 -C6 (NR11 R12 ), C1 -C6 (CONR11 R1 2 ) or C(NR 11 R 12 )NH,

wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p - R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen,

R₂ and A together form a ring of 5-7 atoms,

R₃, R₄ and R₅ are independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, CN, nitro, C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy, aryl, aralkyl, R₁₁O(CH₂)p-, R₁₁C(O)O(CH₂)p-, R₁₁OC(O)(CH₂)p-, -(CH₂)pS(O)nR₁₇, -(CH₂)pC(O)NR₁₁R₁₂ or halogen, wherein R₁₇ is hydrogen, C₁-C₆-alkyl, C₁-C₃-perfluoroalkyl or aryl,

wherein the alkyl and alkenyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₃-alkoxy, wherein the aryl groups are optionally substituted by H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, CN, nitro, C₁-C₆-perfluoroalkyl, C₁-C₆-perfluoroalkoxy, aryl, C₁-C₆-aralkyl, R₁₅O(CR₁₃R₁₄)p-, -R16 C(O)O(CR13 R14 )p-, R15 OC(O)(CR13 R14 )p-, -(CR13 R14 )pS(O)nR12 , (CR13 R2 1;4)pC(O)NR17R18, -(CR13R14)pNR17C(O)R16, -(CR13R14)pN(R17R18), or halogen substituted ,

R₃ and R₄ taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring with 1-3 heteroatoms, selected from N, O and S,

R&sub6; is hydrogen, C1 -C6 alkyl, aryl, C1 -C3 perfluoroalkyl, CN, NO2 , halogen, R11 O(CH2 )p-, NR21 C(O)R2 0 , NR21 C(O)NR20 R21 or SOnR20, where the alkyl groups optionally contain C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1-C6 alkoxy, fluorine, C (O)OR&sub1;&sub5; and aryl-C₁-C₃-alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen,

R�7 is hydrogen or C₁-C₆ alkyl,

wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy,

R&sub8; is C(O)OR20, C(O)NR20 R21 , NR20 R21 , C(O)R20 , NR21 C(O)R20 , NR21 C(O)NR20 R21 , NR20 S(O)2 R21 , NR21 S(O)2 NR20 R21 ;, OC(O)R20, OC(O)NR₂�0;R₂₁, OR₂�0;, SOnR₂�0;, S(O)nNR₂�0;R₂₁, a heterocyclic ring or a bicyclic heterocyclic ring having 1 to 4 heteroatoms, selected from N, O or S, which may optionally be substituted by R₃, R₄ and R₅ or C₁-C₆ alkyl, or

R₇ and R₈ taken together form a heterocyclic ring having one or more heteroatoms selected from N, O or S, which may optionally be substituted by R₃, R₄ and R₅,

R�9 and R9a are independently hydrogen, C₁-C₆ alkyl, aryl, aralkyl when m ≠ 0, wherein the alkyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or

R�9 and R9a taken together form a carbocyclic ring of 3-7 atoms or

form if m ≠ 0,

R�9 and A taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, if m ≠ 0, or

R₁₀ and R10a are independently hydrogen, C₁-C₆ alkyl, aryl or aralkyl, wherein the alkyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or

R₁₀ and R10a taken together form a carbocyclic ring of 3-7 atoms or

form,

R�9 and R₁₀ taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring having one or more heteroatoms when m ≠ 0, or

R�9 and R₂ taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, if m ≠ 0, or

R₁₀ and R₂ taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms,

R₁₀ and A taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, or

R₁₁ and R₁₂ are independently hydrogen, C₁-C₆ alkyl, aryl, aralkyl or a carbocyclic ring of 3-7 atoms,

wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or

R₁₁ and R₁₂ taken together can form an optionally substituted ring of 3-7 atoms,

R&sub1;&sub3; is hydrogen, OH, NR7 R8 , NR11 SO2 (C1 -C6 alkyl), NR11 SO2 (aryl), NR11 SO2 (C1 -C3 perfluoroalkyl ), SO&sub2;NR&sub1;&sub1; (C1 -C6 alkyl), SO2 NR11 (aryl), SO2 NR11 (C1 -C3 perfluoroalkyl), SO2 NR11 (C(O)C1 - C6 alkyl), SO2 NR11 (C(O)-aryl), S(O)n(C1 -C6 alkyl), S(O)n(aryl), C1 -C3 -Perfluoroalkyl, C1 -C3 perfluoroalkoxy, C1 -C6 alkoxy, COOH, halogen, NO2 or CN,

wherein the alkyl groups are optionally substituted by C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or

R₁₄ and R₁₅ are independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, CN, nitro, C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy, aryl, aralkyl, R₁₁O(CH₂)p-, R₁₁C(O)O(CH₂)p-, R₁₁OC(O)(CH₂)p-, -(CH₂)pS(O)nR₁₇, -(CH₂)pC(O)NR₁₁R₁₂ or halogen, wherein R₁₇ is hydrogen, C₁-C₆-alkyl, C₁-C₃-perfluoroalkyl or aryl,

wherein the alkyl and alkenyl groups are optionally substituted by C₁-C₆ alkyl, C3 -C7 cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C1 -C6 alkoxy, fluorine, C(O)OR15 and aryl-C1 -C3 alkoxy are substituted,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or

R&sub1;&sub6; is hydrogen, C1 -C6 alkyl or N(R11 R12 ),

wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy,

R₁₈ is hydrogen, C₁-C₆ alkyl, C(O)OR₁₁, C(O)NR₁₁R₁₂, C(O)R₁₁, S(O)nR₁₁, wherein the alkyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy,

R₁₇ is either the definition of R₁₃ or that of R₁₄,

R₂₀ and R₂₁ are independently hydrogen, C₁-C₆ alkyl, aryl, aralkyl, a carbocyclic ring of 3-7 atoms, a heterocyclic ring or a bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from N, O or S which may optionally be substituted by R₃, R₄ and R₅, C₁-C₆ alkyl substituted by a heterocyclic ring or a bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from N, O or S which may optionally be substituted by R₃, R₄ and R₅,

wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy,

wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or

R₂�0 and R₂₁ taken together can form an optionally substituted ring of 3-7 atoms,

X is N, O, S(O)n, C(O), (CR₁₁R₁₂)p, a single bond to the radical R₈, C₂-C₆-alkenyl, C₂-C₆-alkynyl, where when X is O, S(O)n, C(O) or CR₁₁R₁₂, only R₈ is possible,

Z is O, S or NR₁₁,

m is 0-3,

n is 0-2,

p is 0-4,

wherein the term aryl on each occurrence means phenyl or naphthyl, or a pharmaceutically acceptable addition salt and/or hydrate thereof, or, where applicable, a geometric or optical isomer or a racemic mixture thereof.

Unless otherwise specified, the following definitions shall apply to the entire specification and claims.

If any variable (e.g., aryl, heterocycle, R1, etc.) occurs more than once in any component or in formula I, its definition at each occurrence is independent of its definition at any other occurrence. Likewise, combinations of substituents and/or variables are only permitted if such combinations result in stable compounds.

The term "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g. methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.

The term "aryl" includes phenyl and naphthyl. Preferably, aryl is phenyl.

The term "halogen" or "halo" is intended to include fluorine, chlorine, bromine and iodine.

The term "heterocycle" or "heterocyclic ring" is defined by all non-aromatic heterocyclic rings of 3-7 atoms with 1-3 heteroatoms selected from N, O and S, such as oxirane, oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone and the like.

As used herein, the term "composition" is intended to include a product containing the specified ingredients in the specified amounts and any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts.

In addition, it is well known to those skilled in the art that many of the above heterocyclic groups can exist in more than one tautomeric form. All such tautomers are intended to be included within the scope of this invention.

The optical isomer forms, i.e. mixtures of enantiomers, e.g. racemates, or diastereomers as well as individual enantiomers or diastereomers of the present invention are included. These individual enantiomers are usually designated according to the optical rotation they impart by the symbols (+) and (-), (L) and (D), (l) and (d) or combinations thereof. These isomers can also be designated according to their absolute spatial configuration by (S) and (R), which stand for sinister and rectus, respectively.

The individual optical isomers can be prepared using conventional resolution techniques, e.g. by treatment with an appropriate optically active acid, separation of the diastereomers and subsequent recovery of the desired isomer. In addition, the individual optical isomers can be prepared by asymmetric synthesis.

In addition, a particular chemical formula or chemical name is intended to include pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.

Although active in their own right, the compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable addition salts for the purposes of stability, ease of crystallization, increased solubility and other desirable properties.

The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts. Examples of acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic acid salts and the like, which may be used as a dosage form to modify solubility or hydrolysis properties or may be used in sustained release prodrug formulations. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those derived from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as potassium, magnesium, and zinc. B. ammonia, ethylenediamine, N-methylglutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide. These salts can be formed by standard methods, e.g. by reacting a free acid with a suitable organic or inorganic base. or alternatively by reacting a free base with a suitable organic or inorganic acid.

Also, when an acid (-COOH) or alcohol group is present, pharmaceutically acceptable esters, e.g. methyl, ethyl, butyl, acetate, maleate, pivaloyloxymethyl and the like, and those esters known in the art for modifying solubility or hydrolysis properties for use as prodrug or sustained release formulations may be employed.

The compounds of the present invention may possess other chiral centers besides the centers whose stereochemistry is shown in formula I and therefore exist as racemates, racemic mixtures and as individual enantiomers or diastereomers, all such isomeric forms as well as mixtures thereof being encompassed by the present invention. In addition, some of the crystal forms for the compounds of the present invention may exist as polymorphs and as such are intended to be encompassed by the present invention. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed by the scope of this invention.

The compounds of the invention are prepared by the following reaction schemes. Unless otherwise indicated, all substituents are as defined above. Scheme A

Reaction Scheme A

As shown in Scheme A, treatment of tryptamine (1) with N-carboxyphthalimide in an inert organic solvent such as tetrahydrofuran at a temperature of 20-65°C, preferably 65°C, for 12-48 hours gives the corresponding N-phthalimidotryptamine derivative (2). The N-phthalimidotryptamine (2) could be further modified by treatment with a brominating agent such as pyridinium hydrobromide perbromide, pyrrolidone hydrotribromide or the like in an inert organic solvent such as tetrahydrofuran, methylene chloride, chloroform or mixtures thereof at 0-25°C for 30 minutes to 40 hours to give the 2-bromotryptamine (3). The bromide (3) can be reacted with an arylboronic acid (prepared essentially as described in: Gronowitz, S.; Hornfeldt, A.-B.; Yang, Y.-H. Chem. Scr. 1986, 26, 311-314) under palladium(0) catalysis, a weak base such as aqueous sodium carbonate or the like, and a chloride source such as lithium chloride in an inert solvent such as toluene, benzene, ethanol, propanol or mixtures thereof at a temperature of 25°C-100°C, preferably 80°C, for a period of 1-6 hours to give the 2-aryltryptamine derivative (4). Finally, the phthalimido group can be removed by treatment of (4) with aqueous hydrazine in an inert solvent such as ethyl acetate. B. methanol or ethanol, at a temperature of 2º-25ºC over a period of 4- 24 hours to give tryptamine (5). Scheme B

Reaction Scheme B

As shown in Reaction Scheme B, the 2-aryltryptamine can be condensed with a carboxylic acid of type (6) using the coupling reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof at or near room temperature over a period of 3-24 hours to give the corresponding amide derivative (7). Alternatively, 2-aryltryptamine (5) can be condensed with an active ester or acid chloride of type (8) in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof. B. methylene chloride, chloroform, tetrahydrofuran, diethyl ether or the like, and a tertiary amine such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature of 0 ° C - 25 ° C for 30 minutes to 4 hours to give (7). Scheme C

Reaction Scheme C

As shown in Reaction Scheme C, the amidocarbonyl of (7) can be reduced by treatment with borane, lithium aluminum hydride or equivalent hydride sources in an inert organic solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane or the like at 25°C-100°C, preferably 65°C, for 1-8 hours to give the corresponding amine compound (9). Scheme D

Reaction Scheme D

As shown in Reaction Scheme D, the 2-aryltryptamine (5) can be modified by treatment with an aldehyde or ketone of type (10) in the presence of a weak acid such as trifluoroacetic acid (TFA), acetic acid or the like, with or without a drying agent such as 3Å molecular sieves or magnesium sulfate, and a hydride source such as sodium borohydride or sodium cyanoborohydride in an inert organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, chloroform or mixtures thereof at a temperature of 0°-25°C for a period of 1-12 hours to give the corresponding secondary or tertiary amine derivative (11). Scheme E

Reaction Scheme E

As shown in Reaction Scheme E, treatment of an arylhydrazine or arylhydrazine hydrochloride (12) with an arylcyclopropyl ketone of type (13) in a polar organic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol, at a temperature of 70°-120°C for 8-24 hours gives 2-aryltryptamine (5). Alternatively, 2-aryltryptamine (5) is produced when an arylhydrazine or arylhydrazine hydrochloride (12) is treated with an arylbutyl ketone of type (14) containing a leaving group (chloride, bromide, iodide, O-methanesulfonate, O-trifluoromethanesulfonate or the like) at the 4-position in a polar solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, preferably n-butanol. B. methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol or mixtures thereof, at room temperature for 30 minutes to 2 hours, followed by heating at a temperature of 65º-100ºC for 4-24 hours. Scheme F

Reaction Scheme F

As shown in Reaction Scheme F, iodoanilines of type (15) can be reacted with arylacetylenes, an appropriate palladium(0) catalyst such as tetrakis(triphenylphosphine)palladium, a copper(I) halide such as copper(I) bromide in an inert organic solvent such as triethylamine at a temperature of 50°C-88°C for 30 minutes to 5 hours to give the diarylacetylene (16). The acetylene (16) can be prepared by treatment with a palladium(II) catalyst such as palladium(II) chloride or palladium(II) acetate in an inert organic solvent such as triethylamine. B. acetonitrile, at a temperature of 50º-82ºC for a period of 30 minutes to 6 hours to give 2-arylindole (17). Scheme G

Reaction Scheme G

As shown in Reaction Scheme G, treatment of 2-arylindole (17) with oxalyl chloride neat or in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran or the like at a temperature of 25°-65°C for 3-24 hours gives the acyl chloride adduct (18). The crude product (18) can be reacted with an amine of type (19) in an inert organic solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform or the like and an amine base such as triethylamine, diisopropylethylamine or pyridine at a temperature of 0°C-25°C for 30 minutes to 4 hours to give the amide derivative (20). The amide (20) can be obtained by treatment with a reducing agent such as ethyl acetate. B. borane or lithium aluminum hydride, in an inert organic solvent, such as tetrahydrofuran, at elevated temperatures, preferably at reflux, for a period of 1-5 hours to give compound (21). Scheme H

Reaction Scheme H

As shown in Reaction Scheme H, the N-benzyl derivatives of type (22a) or N-benzyloxycarbonyl derivatives of type (22b) can be reduced to give the secondary amine analogues (7) by treating them with hydrogen (1 atm) and a suitable catalyst such as palladium on carbon, palladium hydroxide on carbon or the like in an inert organic solvent such as tetrahydrofuran, ethyl acetate, methanol, ethanol or mixtures thereof to which a weak acid such as 30% aqueous acetic acid has been added for a period of 10 minutes to 3 hours or until the aryl group has been removed to give the secondary amine. Scheme I

Reaction Scheme I

As shown in Scheme I, treatment of a nitroindole of type (24) with hydrogen (1 atm) and a suitable catalyst such as Raney® nickel in an inert organic solvent such as ethanol, methanol or the like at room temperature for 2-12 hours gives the corresponding aminoindole derivative (25). Scheme J

Reaction Scheme J

As shown in Scheme J, amino- or hydroxyindole (25) can be modified by acylation under a variety of conditions. For example, treatment of (25) with an acid chloride, acid anhydride, or an active ester and an amine base such as triethylamine, diisopropylethylamine, pyridine, or the like in an inert organic solvent such as methylene chloride, chloroform, tetrahydrofuran, or mixtures thereof at 0 °C to room temperature for 1 to 12 hours gives the corresponding amide or ester derivatives (26). Alternatively, (25) can be coupled with a carboxylic acid by one of the many commonly used dehydrating agents. For example, treatment of aminoindole (25) with an appropriate carboxylic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide or mixtures thereof at or near room temperature for 3-24 hours gives the corresponding amide or ester derivative (26). Scheme K

Reaction Scheme K

As shown in Reaction Scheme K, urea or carbamate derivatives of (25) can be prepared by treatment with a carbamoyl chloride of type (27a) or alternatively with an isocyanate reagent of type (27b) and an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0°-65°C for a period of 1-72 hours to give (28). Compound (25) can also be prepared by treatment with a bis(electrophilic) reagent such as phosgene, triphosgene, 1,1'-carbonyldiimidazole, N,N'-disuccinimidyl carbonate or the like with or without the addition of an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or the like in an inert organic solvent such as methylene chloride, chloroform, dimethylformamide, tetrahydrofuran or mixtures thereof at a temperature of 0°-65°C for a period of 1-72 hours to give (28). B. pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, in an inert solvent such as methylene chloride, chloroform or the like at a temperature of -20º-0ºC for a period of 20 minutes to 2 hours. After this time, the reaction mixture is treated with an appropriate mono- or disubstituted amine at -20ºC to 25ºC for a period of 1-5 hours to give the urea or carbamate analogue (28). Scheme L

Reaction Scheme L

As shown in Reaction Scheme L, amine (25) can be modified by treatment with an appropriate sulfonyl chloride of type (29) or sulfamyl chloride of type (30) with an amine base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine in an inert solvent such as methylene chloride, chloroform, dichloroethane or the like at a temperature of -20°-25°C for a period of 20 minutes to 2 hours to give the corresponding N-sulfonamide (31) or N-sulfamylamide derivatives (32), respectively. Scheme M

Reaction scheme M

As shown in Scheme M, the 2-aryltryptamine (33) can be modified by treatment with an epoxide such as (34) in an inert organic solvent such as methanol, ethanol, isopropanol, butanol, tert-butanol or mixtures thereof at a temperature of 65º-110ºC for 8-20 hours to give the corresponding amino alcohol derivative (35). Scheme N

Reaction Scheme N

As shown in Reaction Scheme N, amide derivatives of an acidic indole derivative such as (36) can be prepared by treatment with an appropriate amine (R12R11NH) and an appropriate coupling reagent such as benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and the like, with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base such as N-methylmorpholine (NMM), triethylamine or the like in an inert organic solvent such as ethyl acetate. B. methylene chloride, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof, at or near room temperature over a period of 3-24 hours to give the corresponding amide derivative (37).

The compounds of the present invention are useful for the treatment of various sex hormone-related conditions in men and women. This utility is manifested in their ability to act as antagonists of the neuropeptide hormone GnRH, as demonstrated in the following in vitro assays.

Rat pituitary GnRH receptor binding assay:

Crude plasma membranes prepared from rat pituitary tissues were incubated in a Tris.HCl buffer (50 mM, pH 7.5) containing bovine serum albumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethylamide-GnRH and the desired concentration of a test compound. The assay mixtures were incubated at 4°C for 90-120 minutes, followed by rapid filtration and repeated washing through a glass fiber filter. The radioactivity of the membrane-bound radioligands was determined in a gamma counter. From these data, the IC50 value of radioligand binding to GnRH receptors in the presence of test compound was estimated.

LH release inhibition assay:

Active compounds from the GnRH receptor binding assay were further tested using an in vitro LH release assay to confirm their antagonist activity (blocking of GnRH-induced LH release).

1. Sample preparation

The compounds to be tested were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%.

2. Assay

Male Wistar rats (150-200 grams) were obtained from Charles River Laboratories (Wilmington, MA). Rats were maintained at a constant temperature (25ºC) on a 12-hour light, 12-hour dark cycle. Rat chow and water were available ad libitum. Animals were sacrificed by decapitation and pituitaries were aseptically removed and placed in Hank's balanced salt solution (HBSS) in a 50-ml polypropylene centrifuge tube. The collection tube was centrifuged at 250 x g for 5 minutes and HBSS was removed by stripping. Pituitaries were transferred to a disposable Petri dish and minced with a scalpel. The minced tissue was then transferred to a 50 ml disposable centrifuge tube by suspending the tissue fragments in three consecutive 10 ml aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase. Cell dispersion was carried out in a water bath at 37°C with gentle agitation for 30 minutes. At the end of the incubation, the cells were aspirated 20 to 30 times with a pipette and the undigested pituitary fragments were allowed to settle for 3 to 5 minutes. The suspended cells were removed by aspirating and then subjected to centrifugation at 1200 x g for 5 minutes. The cells were then resuspended in culture medium. The undigested pituitary fragments were digested with 30 ml aliquots of the digestive enzymes as above for a total of 3 digestions. Collagenase/hyaluronidase mixture. The resulting cell suspensions were collected, counted and diluted to a concentration of 3 x 105 cells/ml, and 1.0 ml of this suspension was added to each well of a 24-well dish (Costar, Cambridge, MA). The cells were maintained in a humidified 5% CO2-95% air atmosphere at 37°C for 3 to 4 days. The culture medium consisted of DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% nonessential amino acids, 1% glutamine and 0.1% gentamycin. On the day of an experiment, cells were washed three times 1.5 hours before and two more times immediately before the start of the experiment with DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% fetal bovine serum, 1% nonessential amino acids (100X), 1% glutamine (100X), 1% penicillin/streptomycin (10,000 units of penicillin and 10,000 micrograms of streptomycin per ml), and 25 mM HEPES, pH 7.4. LH release was initiated by adding 1 ml of fresh medium containing test compounds in the presence of 2 nM GnRH to each well in duplicate. Incubation was carried out for 3 hours at 37°C. After incubation, the medium was removed and centrifuged at 2000 x g for 15 minutes to remove all cellular material. The supernatant fluid was removed and its LH content was assayed by a double antibody RIA procedure using materials obtained from Dr. AF Parlow (Harbor-UCLA Medical Center, Torrance, CA).

The compounds of formula I are useful in a number of areas affected by GnRH. They may be useful in sex hormone related conditions, sex hormone dependent carcinomas, benign prostatic hypertrophy or uterine fibroids. Sex hormone dependent carcinomas which may benefit from administration of the compounds of this invention include prostate cancer, uterine cancer, breast cancer and gonadotrophic pituitary adenomas. Other sex hormone dependent conditions which may benefit from administration of the compounds of this invention include endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty. The compounds may also be used in combination with an angiotensin converting enzyme inhibitor such as enalapril or captopril, an angiotensin II receptor antagonist such as morphine or morphine. B. Losartan, or a renin inhibitor to treat uterine fibroids.

The compounds of the invention may also be used for preventing pregnancy as a contraceptive in both men and women, for in vitro fertilization, in the treatment of premenstrual syndrome, in the treatment of lupus erythematosus, in the treatment of hirsutism, in the treatment of irritable bowel syndrome and in the treatment of sleep disorders such as sleep apnea.

Another use of the compounds of this invention is as an adjunct to growth hormone therapy in children with growth hormone deficiency. The compounds can be administered with growth hormone or a compound that increases endogenous production or release of growth hormone. Certain compounds have been developed that stimulate the release of endogenous growth hormone. Peptides known to stimulate the release of endogenous growth hormone include: Growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Publication No. WO 89/07110 and PCT Patent Publication No. WO 89/07111) and GHRP-2 (described in PCT Patent Publication No. WO 93/04081) and hexarelin (J. Endocrinol Invest., 15 (Suppl 9), 45 (1992)). Other compounds that stimulate the release of endogenous growth hormone are disclosed, for example, in the following references: U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; US Patent No. 4,411,890; US Patent No. 5,206,235; US Patent No. 5,283,241; US Patent No. 5,284,841; US Patent No. 5,310,737; US Patent No. 5,317,017; US Patent No. 5,374,721; US Patent No. 5,430,144; US Patent No. 5,434,261; US Patent No. 5,438,136; EPO patent publication No. 0 144 230; EPO patent publication No. 0 513 974; PCT Patent Publication No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; Science, 260, 1640-1643 (June 11, 1993); Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92, 7001-7005 (July 1995).

Representative preferred growth hormone secretagogues used in the present combination include the following:

1) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indole-3 -yl)ethyl]-2-amino-2-methylpropanamide,

2) N-[1(R)-[(1,2-Dihydro-1-methanecarbonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indole-3 -yl)ethyl]-2-amino-2-methylpropanamide,

3) N-[1(R)-[(1,2-Dihydro-1-benzenesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indole-3 -yl)ethyl]-2-amino-2-methylpropanamide,

4) N-[1(R)-[(3,4-Dihydrospiro[2H-1-benzopyran-2,4'-piperidin]-1'-yl)- carbonyl]-2-(1H-indole-3- yl)ethyl]-2-amino-2-methylpropanamide,

5) N-[1(R)-[(2-acetyl-1,2,3,4-tetrahydrospiro[isoquinolin-4,4'-piperidine]-1'-yl)carbonyl]-2-(indole-3 -yl)ethyl]-2-amino-2-methylpropanamide,

6) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indol-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]- 2-amino-2-methylpropanamide,

7) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indol-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]- 2-amino-2-methylpropanamide methanesulfonate,

8) N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidine]-1'-yl)carbonyl]-2-(2',6' -difluorophenylmethyloxy)ethyl]-2-amino-2-methylpropanamide,

9) N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-5-fluorspiro[3H-indol-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy )ethyl]-2-amino-2-methylpropanamide,

10) N-[1(S)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethylthio)ethyl]- 2-amino-2-methylpropanamide,

11) N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-phenylpropyl]-2-amino -2-methylpropanamide,

12) N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino -2-methylpropanamide,

13) N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino -2-methylpropanamide,

14) N-[1(R)-[(1,2-dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidine)-1'-yl)carbonyl]-2-(5-fluoro-1H -indol-3-yl)ethyl]-2-amino-2-methylpropanamide,

15) N-[1(R)-[(1,2-dihydro-1-methanesulfonyl-5-fluorspiro[3H-indol-3,4'-piperidin)-1'-yl)carbonyl]-2-(5 -fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide,

16) N-[1(R)-[(1,2-Dihydro-1-(2-ethoxycarbonyl)methylsulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-( 1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide,

17) N-[1(R)-[(1,2-dihydro-1,1-dioxospiro[3H-benzothiophene-3,4'-piperidin]- 1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide, and pharmaceutically acceptable salts thereof.

The compounds of the invention can also be used in combination with bisphosphonates (bisphosphonic acids) and other agents, such as growth hormone secretagogues, e.g. MK-0677, for the treatment and prevention of disorders of calcium, phosphate and bone metabolism, in particular to prevent bone loss during therapy with the GnRH antagonist, and in combination with estrogens, progesterones and/or androgens to prevent or treat bone loss or hypogonadal symptoms, such as hot flushes, during therapy with the GnRH antagonist.

Bisphosphonates (bisphosphonic acids) are known to inhibit bone resorption and are useful for treating bone lithiasis, as disclosed in US Patent 4,621,077 to Rosini et al.

The literature discloses a number of bisphosphonic acids useful in the treatment and prevention of diseases associated with bone resorption. Representative examples can be found in the following references: U.S. Patent No. 3,251,907; U.S. Patent No. 3,422,137; U.S. Patent No. 3,584,125; U.S. Patent No. 3,940,436; U.S. Patent No. 3,944,599; U.S. Patent No. 3,962,432; U.S. Patent No. 4,054,598; U.S. Patent No. 4,267,108; U.S. Patent No. 4,327,039; U.S. Patent No. 4,407,761; US Patent No. 4,578,376; US Patent No. 4,621,077; US Patent No. 4,624,947; US Patent No. 4,746,654; US Patent No. 4,761,406; US Patent No. 4,922,007; US Patent No. 4,942,157; US Patent No. 5,227,506; US Patent No. 5,270,365; EPO patent publication No. 0 252 504 and J. Org. Chem., 36, 3843 (1971).

The preparation of bisphosphonic acids and halobisphosphonic acids is well known in the art. Representative examples can be found in the above-mentioned references, which disclose the compound as being suitable for treating disorders of calcium or phosphate metabolism, in particular as inhibitors of bone resorption.

Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid, etidronic acid, clodronic acid; pamidronic acid, tiludronic acid, risedronic acid, 6-amino-1-hydroxyhexylidenebisphosphonic acid and 1-hydroxy-3-(methylpentylamino)-propyldienebisphosphonic acid; or any pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is alendronic acid (alendronate) or a pharmaceutically acceptable salt thereof. A most particularly preferred bisphosphonate is alendronate sodium, including alendronate sodium trihydrate. Alendronate sodium has received approval for marketing in the United States under the trademark FOSAMAX®.

In addition, a compound of the present invention may be administered together with a 5α-reductase-2 inhibitor such as finasteride or epristeride, a 5α-reductase-1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one, 3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane and 3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as disclosed in WO 93/23420 and WO 95/1125A, with dual inhibitors of 5α-reductase 1 and 5α-reductase 2, such as 3-oxo-4-aza-17β-(2,5-trifluoromethylphenylcarbamoyl)-5α-androstane as disclosed in WO 95/07927, with antiandrogens such as flutamide, casodex and cyproterone acetate, and with alpha-1 blockers such as prazosin, terazosin, doxazosin, tamsulosin and alfuzosin.

Furthermore, a compound of the present invention can be used in combination with growth hormone, growth hormone releasing hormone or growth hormone secretagogues to delay puberty in children with growth hormone deficiency, thereby allowing them to continue to gain height prior to fusion of the epiphyses and cessation of growth at puberty.

For combination treatment with more than one active ingredient, where the active ingredients are presented in separate dosage formulations, the active ingredients may be administered separately or together. In addition, the administration of one element may occur before, simultaneously or after the administration of the other agent.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example as tablets, lozenges, medicated biscuits, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any process known in the art for preparing pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavourings, colouring agents and preservatives to give pharmaceutically tasty and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may, for example, be inert diluents such as. B. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch or alginic acid, binding agents, for example starch, gelatin or acacia, and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known methods to delay dissolution and absorption in the gastrointestinal tract and thereby provide a delayed effect over a longer period of time. For example, a time delay material such as glycerol monostearate or glycerol distearate may be used. They may also be coated by the methods described in US Patents 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredient in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as e.g. B. polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavorings and one or more sweeteners, such as e.g. sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil, such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and flavorings may be added to give a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and Suspending agents are those already mentioned above. Additional excipients, such as sweeteners, flavourings and colourings, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifiers may be naturally occurring phosphatides, for example soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavourings.

Syrups and elixirs may be formulated with sweeteners, for example glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavors and colors.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. Any bland fixed oil may be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as e.g. B. Oleic acid, used in the manufacture of injectable preparations.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but is liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or Suspensions, etc., containing the compound of formula I (for the purposes of this application, topical application is intended to include mouthwashes and gargles).

The compounds of the present invention can be administered in intranasal form by topical application of suitable intranasal vehicles or by transdermal routes using those forms of transdermal patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dose administration will, of course, be continuous rather than intermittent throughout the dosing regimen. The compounds of the present invention can also be delivered as a suppository using bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention is selected according to a variety of factors, including the type, species, age, weight, sex and medical condition of the patient, the severity of the condition being treated, the route of administration, the renal and hepatic function of the patient, and the particular compound used. A physician or veterinarian of ordinary skill can determine and prescribe the effective amount of drug needed to prevent, arrest or reverse the progression of the condition. The optimal accuracy in achieving a drug concentration within the range that produces an effect without toxicity requires a regimen based on the kinetics of drug availability to the target sites. This includes consideration of the distribution, equilibrium and elimination of a drug. Preferably, doses of the compound of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult per day. More preferably, doses range from 0.1 to 500 mg/day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1000 milligrams of active ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of active ingredient, for symptomatic adjustment of the dose to the patient being treated. An effective amount of the drug is normally provided at a dose concentration of from about 0.0002 mg/kg to about 50 mg/kg body weight per day. The range is specifically about 0.001 mg/kg to 1 mg/kg body weight per day.

Advantageously, the active ingredient of the present invention can be a single dose, or the total daily dose may be given in divided doses two, three, or four times a day.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the specific route of administration.

It will be understood, however, that the specific dosage concentration for any particular patient will depend on a number of factors, including age, body weight, general health, sex, diet, time of administration, duration of administration, rate of excretion, drug combination and the severity of the specific condition for which therapy is being administered.

The following examples illustrate the preparation of some of the compounds of the invention and are not to be construed as limiting the invention disclosed herein. EXAMPLE 1 [2-(3,5-Dimethylphenyl)-3-[2-(4-pyridin-4-ylbutylamino)ethyl]-1H-indol-5-yl]morpholin-4-ylmethanone

Step 1A 3-(2-Aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester

A mixture of 7.60 g (50 mmol) of 4-hydrazinobenzoic acid, 10.55 g (50 mmol) of 3-chloropropyl-3,5-dimethylphenyl ketone and 200 mL of absolute ethanol was stirred under nitrogen and heated to reflux. After 12 hours, the mixture was cooled and filtered. The solid on the filter was washed with additional small volumes of ethanol. The filtrate was treated with 4 mL of concentrated sulfuric acid and stirred at reflux under nitrogen for 4 days. The cooled mixture was stirred in an ice bath as a solution of sodium ethoxide (21% w/w in ethanol) was added dropwise until the mixture was basic by pH paper. The mixture was filtered and concentrated in vacuo at 30 °C. The residue was partitioned between diethyl ether and water, adding some saturated aqueous sodium chloride solution to aid in separation of the layers. The aqueous phase was washed with an additional 100 mL of ether. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residual gum was purified by flash chromatography on silica gel (eluting with 97:3:0.3 and then 95:5:0.5 methylene chloride:methanol:ammonium hydroxide) to give the title compound (4.8 g). 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3 /CI): m/e = 337 (M + H).

Step 1B 2-(3,5-Dimethylphenyl)-3-[2-[4-(pyridin-4-yl)butylamino]ethyl]-1H-indole-5-carboxylic acid ethyl ester

To a dry flask were added 5.0 g (14.9 mmol) of ethyl 3-(2-aminoethyl)- 2-(3,5-dimethylphenyl)-1H-indole-5-carboxylate, 1.98 g (13.5 mmol) of 4-(pyridin-4-yl)butyraldehyde (diluted with 0.5 mL of CDCl3), 8.12 g (67.7 mmol) of anhydrous magnesium sulfate, and a magnetic stir bar. The flask was purged with nitrogen, cooled to -10 °C, and stirred as 11.5 mL of dry CDCl3 was gradually added via syringe. The mixture was stirred under nitrogen for about 20 minutes. The septum was then removed and 670 mg (17.6 mmol) of sodium borohydride was added rapidly. The septum was immediately replaced and the system again flushed with nitrogen. The mixture was stirred at approximately -5 °C under nitrogen as 10 mL of dry methanol was gradually added via syringe. After a few minutes at this temperature, the reaction was removed from the cooling bath and partitioned between 80 mL of ethyl acetate and 100 mL of water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with a gradient of 4-9% methanol in methylene chloride; repeated using 5-15% methanol in methylene chloride) to give the title compound (3.19 g). 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (PB-NH3/Cl): m/e = 470.4 (M + H). An additional 1.91 g of less pure material was also isolated.

Step 1C 3-[2-[Benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]- 2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester

A solution of 3.19 g (6.83 mmol) of ethyl 2(3,5-dimethylphenyl)3[2-[4- (pyridin-4-yl)butylamino]ethyl]-1H-indole-5-carboxylate in 25 mL of dry methylene chloride was stirred under nitrogen and cooled to -78 °C in a dry ice-acetone bath when 2.38 mL (1.76 g, 13.7 mmol) of N,N-diisopropylethylamine was added, followed by the gradual portionwise addition of 3.4 mL (4.06 g, 23.7 mmol) of benzyl chloroformate via syringe. After about 2.5 hours, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% aqueous potassium hydrogen sulfate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (eluting with a gradient of 0.5-10% methanol in methylene chloride) gave a quantitative yield of the product as a yellow foam. The 500 MHz 1H NMR was complex due to the existence of rotamers but was consistent with the assigned structure. Mass spectrum (PB-NH3/Cl): m/e = 604.3 (M + H).

Step 1D 3-[2-[Benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2- (3,5-dimethylphenyl)-1H-indole-5-carboxylic acid hydrochloride

A solution of ethyl 3-[2-[benzyloxycarbonyl-[4- (pyridin-4-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylate (4.11 g, 6.83 mmol) in 0.50 N KOH (161 mL, 80.5 mmol) in methanol was stirred at about 60 °C as 19 mL of water was gradually added. Stirring was continued at reflux overnight. The cooled mixture was concentrated in vacuo to give a yellow solid which was partitioned between 250 mL of a 1:1 ethyl acetate-tetrahydrofuran mixture and 250 mL of 0.5 N Ed. The organic phase was washed twice with 0.5 N HCl, then dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated with diethyl ether and collected on a filter to give (after drying) 3.46 g of yellow solid, mp 133.5-137.5 °C; homogeneous by TLC (95:5:0.5 CH2Cl2-MeOH-AcOH). 500 MHz 1H NMR (DMSO-d6) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 576.4 (M + H)+.

Step 1E [2-[2-(3,5-Dimethylphenyl)-5-(morpholin-4-carbonyl)-1H-indol- 3-yl]ethyl]-(4-pyridin-4-ylbutyl)carbamic acid benzyl ester

A mixture of 100 mg (0.163 mmol) 3-[2-[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid hydrochloride, 101.7 mg (0.196 mmol) PyBOP reagent, 0.085 mL (85.2 mg, 0.978 mmol) morpholine and 1 mL dry methylene chloride was under nitrogen at room temperature in a sealed flask. After 5 days, the solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-4% MeOH in CH2Cl2) gave a quantitative yield of the title compound as a yellow gum; homogeneous by TLC in 95:5 CH2Cl2-MeOH. The 500 MHz 1H NMR (CDCl3) was complex due to rotamers, but consistent with the assigned structure. Mass spectrum (ESI): m/e = 645.6 (M + H).

Step 1F [2-(3,5-Dimethylphenyl)-3-[2-(4-pyridin-4-ylbutylamino)ethyl]- 1H-indol-5-yl]morpholin-4-ylmethanone

A mixture of benzyl [2-[2-(3,5-dimethylphenyl)-5- (morpholin-4-carbonyl)-1H-indol-3-yl]ethyl]-(4-pyridin-4-ylbutyl)carbamic acid ester (113 mg, 0.175 mmol), 20% palladium hydroxide on carbon (50 mg), and 2-methoxyethanol (10 mL) was shaken with hydrogen (approximately 50 psig) in a pressure vessel for 2.5 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution from 99:1:0.1 to 94:6:0.6 CH2Cl2-MeOH-conc. NH4OH) to give 53.2 mg (60%) of a white stiff foam; homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-conc. NH4OH. The 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 511.5 (M + H).

PRODUCTION OF SYNTHESIS INTERMEDIATES Step A: 4-(4-pyridyl)-3-pentyn-1-ol

4-Bromopyridine hydrochloride salt (5.5 g) was dissolved in a solvent mixture containing triethylamine (50 mL) and water (10 mL). Anhydrous lithium chloride (100 mg), copper(I) bromide powder (100 mg) and but-3-yn-1-ol (2.17 g) were added to the pyridine salt and the mixture was stirred as an active stream of nitrogen gas was gently bubbled through the solution for about 15 minutes, after which tetrakis(triphenylphosphine)palladium (250 mg) was added. The reaction mixture was heated to reflux under a nitrogen atmosphere and kept at reflux for 2.5 hours, after which heating was stopped and the reaction was allowed to cool to room temperature. The mixture was concentrated in vacuo and the residue was treated with 3º sodium hydroxide, extracted with chloroform and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (ethyl acetate) gave the title compound (3.74 g).

Step B: 4-(4-pyridyl)butan-1-ol

4-(4-Pyridyl)-3-butan-1-ol (3.5 g) was dissolved in methanol (100 mL) in a Parr hydrogenation flask and platinum(IV) oxide [Adam's catalyst] (0.3 g) was added. The Parr flask was placed on a Parr hydrogenation apparatus and the solution was hydrogenated at 40 psi for 2.5 h, after which the starting material was considered spent by TLC. The spent catalyst was removed by filtration through a pad of Celite and the pad was washed thoroughly with additional methanol. The combined filtrates were evaporated under reduced pressure on a rotary evaporator and the oily residues were then subjected to column chromatography on a short column of silica using neat ethyl acetate as the eluent to give the title compound (3.0 g).

Step C: 4-(pyridin-4-yl)butyraldehyde

Oxalyl chloride (1.45 mL of a 2 M solution in dry methylene chloride) was added to an oven dried flask and cooled to -78°C with a dry ice-acetone bath, and a solution of DMSO (0.413 mL) in dry methylene chloride (1 mL) was added drop by drop to the oxalyl chloride over 3 minutes and stirring was continued for 3 minutes. A solution of 4-(4-pyridyl)butan-1-ol (400 mg) in dry methylene chloride (5 mL) was added to the reaction flask over about 3 minutes and the reaction was stirred for 15 minutes. Anhydrous triethylamine (2.03 mL) was added and the reaction mixture was stirred for an additional 2 hours, during which time the cooling bath had warmed to room temperature. The reaction was quenched by the addition of saturated brine and then partitioned with methylene chloride. The aqueous layer was discarded and the methylene chloride extract was dried over anhydrous sodium sulfate powder, filtered and evaporated under reduced pressure to leave an oily residue. The product was isolated by column chromatography on silica gel using ethyl acetate as eluant (301 mg).

By following a procedure similar to that described in EXAMPLE 1, the following compounds were prepared: EXAMPLE 2 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[4-(4-pyridin-3-yl)butylamino]ethyl]-1H-indol-5-yl]-2-methylpropan-1-one dihydrochloride

Step 2A Ethyl 2-[2-(3,5-Dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]- ethyl]-1H-indol-5-yl]-2-methylpropionate

A dry flask containing 3.00 g (7.93 mmol) of ethyl 2-(3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionate (prepared essentially as described in EXAMPLE 1 from ethyl 2-(4-hydroxazinophenyl)-2-methylpropionate), 4.76 g (39.7 mmol) of anhydrous magnesium sulfate, and a magnetic stir bar was fitted with a septum and a needle adapter leading to a Firestone valve. The flask was thoroughly purged with nitrogen, and the mixture was cooled to -10 to -5 °C in an ice-methanol bath and stirred vigorously as a solution of 1.32 g (8.88 mmol) of 4-pyridin-3-yl)butyraldehyde in 15 mL of dry CDCl₃ was gradually added via syringe over 10-15 minutes. The resulting mixture was stirred under nitrogen at -10 to -5 °C for 40-45 minutes. The septum was then removed just long enough to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under nitrogen at -10 to -5 °C while dry methanol was added dropwise via syringe over several minutes. After 30 minutes, the mixture was removed from the cooling bath and partitioned between 90 mL of ethyl acetate and 90 mL of water. The organic layer was washed with 2 x 30 mL of brine, then dried over anhydrous sodium sulfate. The filtered solution was concentrated in vacuo and the residue was flash chromatographed on silica gel (gradient elution with 0-10% methanol in methylene chloride). The fractions containing the product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of light beige stiff foam, which was used directly in the next step without further purification or characterization.

Step 2B 2-[3-[2-Benzyloxycarbonyl-[4-(pyridin-3-yl)butyl]amino]ethyl]- 2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester

A solution of 3.00 g (max. 5.86 mmol) of crude ethyl 2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]ethyl]-1H-indol-5-yl]-2-methylpropionate in 30 mL of dry methylene chloride was stirred under nitrogen with cooling in a dry ice-acetone bath. To this solution was added 1.106 mL (820 mg, 6.36 mmol) of N,N-diisopropylethylamine via syringe. Then 0.956 mL (1.14 g, 6.36 mmol) of benzyl chloroformate was added dropwise over 5-10 minutes via syringe. After 20 minutes, the solution was removed from the cooling bath and allowed to warm to room temperature. After 2 hours, the solution was diluted with 50 mL of methylene chloride, transferred to a separatory funnel, and shaken with 80 mL of water. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the remaining gum on silica gel (gradient elution with 0.2-2% methanol in methylene chloride) afforded 2.81 g (55% total for steps 1 and 2) of pale golden-yellow gum; nearly homogeneous by TLC in 95:5 CH2Cl2-MeOH. The 500 MHz 1H NMR (CDCl3) was complex due to rotamers, but appeared consistent with the assigned structure. Mass spectrum (ESI): m/e = 646 (M + H).

Step 2C 2-[3-[2-[Benzyloxycarbonyl-[4-(pyridyn-3yl)butyl]amino]-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2- methyl propionic acid

A mixture of 2.78 g (4.30 mmol) of ethyl 2-[3-[2-[benzyloxycarbonyl-[4- (pyridin-3-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionate in 43.0 mL (21.5 mmol) of 0.5 M potassium hydroxide in methanol and 25 mL of tetrahydrofuran was stirred under nitrogen and heated to reflux. To the resulting solution was gradually added 18 mL of water and the solution was kept at reflux for 39 hours. It was then cooled and concentrated to a small volume, accompanied by the formation of a precipitate. The mixture was treated with 10.75 mL (21.5 mmol) of 2 N hydrochloric acid and stirred for a few minutes. The solution was collected on a filter and washed thoroughly with water. After suction drying under nitrogen, the solid was triturated with diethyl ether and washed and vacuum dried to give 2.43 g (92%) of cream powder, mp 152-154 °C (partially dec.); homogeneous by TLC in 90:10 CH2Cl2-MeOH. The 500 MHz 1H NMR (DMSO-d6) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 618 (M + H).

Step 2D [2-[5-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H- indol-3-yl]ethyl]-[4-(pyridin-3-yl)butyl]carbamic acid benzyl ester

A mixture of 92.7 mg (0.15 mmol) of 2-[3-[2-[benzyloxycarbonyl-[4-(pyridin-3-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid, 80.2 mg (0.6 mmol) of 7-azabicyclo[2.2.1]heptane hydrochloride, 83.2 mg (0.16 mmol) of PyBOP reagent, 0.107 mL (77.8 mg, 0.77 mmol) of triethylamine, and 0.75 mL of dry methylene chloride was stirred in a sealed flask at room temperature for 48 hours. The solution was then partitioned between 10 mL of ethyl acetate and 10 mL of 0.5 N hydrochloric acid. The organic phase was washed with 10 mL of saturated aqueous sodium bicarbonate solution and then with 5 mL of saturated aqueous sodium chloride solution. The ethyl acetate phase was then dried (magnesium sulfate), filtered and concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 6 Analtech tapered silica plates (20 x 20 cm) developed in 95:5 CH2Cl2-MeOH. The product band from each plate was isolated, combined and extracted with 95:5 CH2Cl2-MeOH. Concentration of the extracts in vacuo gave 85.9 mg (82%) of a very pale yellow glass; practically homogeneous by TLC in 95:5 CH2Cl2-MeOH. The 500 MHz ¹H NMR (CDCl₃) was complex due to rotamers, but was consistent with the assigned Structure. Mass spectrum (ESI): m/e = 697.6 (M + H).

Step 2E 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino] ethyl]-1H-indol-5-yl]-2-methylpropan-1-one

A mixture of 80.2 mg (0.115 mmol) of [2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H- indol-3-yl]ethyl]-[4-(pyridin-3-yl)butyl]carbamic acid benzyl ester, 40 mg of 10% palladium on carbon, 4 mL of absolute ethanol, and 4 mL of ethyl acetate was shaken with hydrogen (46 psig) in a pressure vessel for 6 h. The catalyst was removed by filtration through Celite under nitrogen and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 4 Analtech tapered silica plates (20 x 20 cm) developed in 92.5:7.5:0.75 CH2Cl2-concentrated NH4OH. The product band from each plate was isolated, pooled and extracted with 92.5:7.5:0.75 CH2Cl2-MeOH-concentrated NH4OH. Concentration of the extracts in vacuo gave 53.8 mg (81%) of a pale yellow, stiff gum or glass; essentially homogeneous by TLC in 92.5:7.5:0.75 CH2Cl2-MeOH-concentrated NH4OH. The 500 MHz 1H NMR (CDCl₃) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 563.5 (M + H).

Step 2F 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino] ethyl]-1H-indol-5-yl]-2-methylpropan-1-one dihydrochloride

A solution of 42.8 mg (0.0760 mmol) of 1-(7-azabicyclo[2.2.1]hept-7- yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]ethyl]-1H- indol-5-yl]-2-methylpropan-1-one in 1.5 mL of methanol was treated with 0.152 mL (0.304 mmol) of 2 N hydrochloric acid. The solution was stirred and allowed to stand briefly before filtering. The filtrate was evaporated to dryness under nitrogen and the residue was triturated with diethyl ether. The resulting solid was collected on a filter, washed with additional ether, and dried to give 46.5 mg (96%) of light golden brown powder, mp > 160 °C (stepwise; pre-softening). The 500 MHz 1H NMR (DMSO-d6) was consistent with the assigned structure.

PRODUCTION OF SYNTHESIS INTERMEDIATES Step A: Ethyl (+/-)-2-(4-nitrophenyl)propionate

To a solution of 9.76 g (50 mmol) of (+/-) 2(4-nitrophenyl)propionic acid in 150 mL of absolute ethanol was added 3.0 mL of concentrated sulfuric acid. The resulting solution was stirred at reflux under nitrogen. After 6 hours, the solution was cooled and stirred vigorously as 250 mL of saturated aqueous sodium bicarbonate solution was gradually added (caution: effervescence). The mixture was then partitioned between 750 mL of ethyl acetate and 500 mL of water. The organic layer was washed with 100 mL of saturated aqueous sodium bicarbonate solution and then with 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 10.86 g (97%) of an oil; homogeneous by TLC in 9:1 hexane-ethyl acetate. The 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure.

Step B: Ethyl 2-methyl-2-(4-nitrophenyl)propionate

A suspension of 924 g (23 mmol) of sodium hydride (60% in oil) in 21 mL of dry N,N-dimethylformamide was stirred under nitrogen in an ice bath as a solution of 4.68 g (21 mmol) of ethyl (+/-)-2-(4-nitrophenyl)propionate in 20.5 mL of dry N,N-dimethylformamide was gradually added over about 10 minutes. An intense violet color developed during the addition. The mixture was then allowed to warm to room temperature. After about 1 hour, the mixture was again cooled in an ice bath and a solution of 1.44 mL (3.28 g, 23 mmol) of methyl iodide in 5 mL of dry N,N-dimethylformamide was added dropwise via syringe over about 10 minutes, keeping the internal temperature at 10-15 °C. The mixture was allowed to warm to room temperature and the color changed to brown. After 1 hour, an additional 187 mL (426 mg, 3 mmol) of iodomethane was added. The next day, the mixture consisted of a suspension of some grayish solid in a golden liquid. It was stirred vigorously and quenched by the gradual addition of 10 mL of 5% aqueous potassium hydrogen sulfate solution. The mixture was partitioned between 400 mL of diethyl ether and 400 mL of water. The organic layer was washed with an additional 3 x 400 mL of water followed by 50 mL of saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography of the residue on silica gel (eluting with 19:1 hexane-ethyl acetate) gave 4.31 g (87%) of an oil; homogeneous by TLC in 9:1 hexane-ethyl acetate. The 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure.

Step C: Ethyl 2-(4-aminophenyl)-2-methylpropionate

A mixture of 4.27 g (18 mmol) of ethyl 2-methyl-2-(4-nitrophenyl)propionate, 200 mg of 10% palladium on carbon, and 120 mL of absolute ethanol was shaken with hydrogen (initial hydrogen pressure 47 psig) in a pressure vessel for 2 h. The catalyst was removed by filtration through celite under nitrogen and the filter cake was washed with additional ethanol. Concentration of the filtrate in vacuo at up to 50 °C gave 3.74 g (100%) of an oil; homogeneous by TLC in 4:1 hexane-EtOAc. The 400 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 208 (M + H).

Step D: Ethyl 2-(4-hydrazinophenyl)-2-methylpropionate

A solution of 3.725 g (18 mmol) of ethyl 2-(4-aminophenyl)-2-methylpropionate in 18 mL of concentrated hydrochloric acid was stirred at -10 to -5 °C in an ice-acetone bath when a solution of 1.29 g (18.7 mmol) of sodium nitrite in 7.5 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. A small amount of insoluble solid was then removed by filtration into a cold receiving flask. The filtrate was then added dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of stannous chloride dihydrate in 14.5 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about -5ºC. A gummy material separated during the addition. After the addition was complete, stirring was continued for 1 hour at -10 to -5ºC. The aqueous phase was decanted and the remaining gum dissolved in 250 mL of ethyl acetate. The ethyl acetate solution was carefully treated with 250 mL of saturated aqueous sodium bicarbonate solution and shaken in a separatory funnel. The ethyl acetate layer was washed with 50 mL of saturated aqueous sodium chloride solution. The entire mixture was filtered before separating the phases. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated in vacuo at room temperature to give 2.59 g (65%) of an oil. The 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure and showed that only minor impurities were present.

By following a procedure similar to that described in EXAMPLE 2, the following compounds were prepared: EXAMPLE 3.1 5-[2-(3,5-Dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]ethyl-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one

Step 3.1A 2-Ethyl-4,4-dimethyl-5-(4-nitrophenyl)-2,4-dihydropyrazol-3-one

A mixture of 1.00 g (4 mmol) of methyl 2,2-dimethyl-3-(4-nitrophenyl)-3-oxopropionate (Yang, C.-Y.; Wnek, GE, Polymer, 1992, 33 4191-4196), 3.00 g (20 mmol) of ethyl hydrazine oxalate, 8 mL of 2-methoxyethanol, and 4 mL of glacial acetic acid was stirred under nitrogen at gentle reflux for 24 hours. The cooled solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with additional water and then with saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 703 mg (67%) of light yellow crystals, mp 121-122 °C; homogeneous by TLC in 2:1 hexane-EtOAc. The 500 MHz ¹H NMR (CDCl₃) was consistent with the assigned Structure. Mass spectrum (PB-NH₃/Cl): m/e = 232.1 (M-Et), 265.1 (M + H).

Step 3.1B 5-(4-Aminophenyl)-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one

Hydrogenation of 2-ethyl-4,4-dimethyl-5-(4-nitrophenyl)-2,4-dihydropyrazol-3-one according to the procedure of Example 3.2, Step E, gave a quantitative yield of light tan solid, mp 118-120.5 °C; homogeneous by TLC in 1:1 hexane-EtOAc and 98:2 CH2Cl2-MeOH. The 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 232.1 (M + H).

Step 3.1C 2-Ethyl-5-(4-hydrazinophenyl)-4,4-dimethyl-2,4-dihydropyrazol-3-one

This material was prepared from 5-(4-aminophenyl)-2-ethyl-4,4-dimethyl- 2,4-dihydropyrazol-3-one according to the procedure of Example 2 REACTION INTERMEDIATES, Step D, except that the entire reaction mixture from the stannous chloride reduction was stirred in an ice bath and carefully treated with an excess of saturated sodium carbonate solution (CAUTION: foaming) which resulted in the formation of a precipitate. This material was transferred to a separatory funnel and shaken with 2:1 Et2O-CH2Cl2. The mixture was filtered prior to phase separation. The aqueous phase was further extracted with several portions of ethyl acetate. The combined organic fractions were concentrated in vacuo to give an 80% yield of an amorphous light yellow-orange solid, mp 131.5-135 °C dec.; poorly defined by TLC in 95:5 CH2Cl2-MeOH. The 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure.

Step 3.1D 5-[3-(2-Aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazole-3 -on

This compound was prepared from 2-ethyl-5-(4-hydrazinophenyl)-4,4-dimethyl-2,4-dihydropyrazol-3-one and 3-chloropropyl-3,5-dimethylphenyl ketone according to the procedure of Example 3.2, Step A, except the reaction time was 15 hours. Flash chromatography of the crude product on silica gel (gradient elution with 97:3 and 95:5 CH2Cl2-MeOH, followed by 95:5:0.5 and 92.5:7.5:0.75 CH2Cl2-MeOH-conc. NH4OH) gave a 27% yield of light tan stiff foam; homogeneous by TLC in 92.5:7.5:0.75 CH₂Cl₂-MeOH-conc. NH₄OH. 500 MHz 1H NMR (CDCl₃) was consistent with the assigned structure. Mass spectrum (PB-NH₃/Cl): m/e 403.2 (M + H).

Step 3.1E 5-[2-(3,5-Dimethylphenyl)-3-[2-[4-(pyridin-3-yl)butylamino]ethyl-1H-indol-5-yl]-2-ethyl-4, 4-dimethyl-2,4-dihydropyrazol-3-one

A mixture of 82.5 mg (0.205 mmol) of 5-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one and 124 mg (0.475 mmol) of magnesium sulfate was purged with nitrogen and stirred in an ice-methanol bath at about -10 to -5 °C when a solution of 34.3 mg (0.23 mmol) of 4-(pyridin-4-yl)butyraldehyde in 0.500 mL of dry CDCl₃ was gradually added via syringe. The mixture was stirred under nitrogen at this temperature for 30 min. The septum was removed just long enough to add 10.0 mg (0.265 mmol) of sodium borohydride and the solution was again purged with nitrogen. The mixture was stirred at -10 to -5 °C when 350 mL of dry methanol was gradually added and stirring was continued at this temperature. After 45 minutes the mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC on 6 1000 micron silica gel GF plates (developed in 87.5:12.5 CH2Cl2-MeOH). Isolation of the product band (by extraction with 90:10:1 CH2Cl2-MeOH-conc. NH4OH) gave 49.8 mg (45%) of a light beige stiff foam; essentially homogeneous by TLC in 90:10 CH₂Cl₂-MeOH. The 500 MHz 1H NMR (CDCl₃) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 536.4 (M + H). EXAMPLE 3.2 1-{2-(2,3-Dimethylphenyl)-3-[2-(4-pyridin-3-ylbutylamino)ethyl]-1H-indol-5-yl}-4-methyl-1,4-dihydrotetrazol-5-one

Step 3.2A 2-[2-(3,5-Dimethylphenyl)-5-nitro-1H-indol-3-yl]ethylamine

To a solution of 3-chloropropyl-3,5-dimethylphenyl ketone (2.5 g in The mixture was stirred at room temperature for 20 minutes. At this time, 108 mL of 90% aqueous methanol was added and the mixture was heated to reflux in an oil bath. After 16 hours, the mixture was cooled to room temperature and the volatiles were removed in vacuo. The residue was triturated with ethyl acetate and left at 0 °C for 8 hours. Filtration of the resulting suspension gave the crude title compound as the hydrochloride salt (1.4 g).

Step 3.2B N-{2-[2-(3,5-Dimethylphenyl)-5-nitro-1H-indol-3-yl]- ethyl)benzamide

To a solution of 2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethylamine (3.0 g in 80 mL of dry methylene chloride) at 0 °C was added 4.0 mL of triethylamine followed by 1.4 mL of benzoyl chloride and the mixture was stirred at low temperature. After 20 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with water and concentrated in vacuo to give the crude title compound (1.43 g).

Step 3.2C Benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3- yl]ethyl}amine

To a stirred solution of N-{2-[2-(3,5-dimethylphenyl)-5-nitro- 1H-indol-3-yl]ethyl}benzamide (1.7 g in 130 mL of dry tetrahydrofuran) was added 35 mL of a 1 M solution of borane in tetrahydrofuran and the mixture was slowly heated to reflux in an oil bath. After 2 h, the mixture was cooled to room temperature and the excess borane was quenched by careful addition of methanol. The mixture was concentrated to half its volume, treated with N,N-dimethylethanolamine (13 mL) and heated to reflux in an oil bath. After 3 h, the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (1.5 g).

Step 3.2D Benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl]-(4-pyridin-3-ylbutyl)amine

A mixture of benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl)amine (700 mg) and 4-pyridin-3-ylbutyraldehyde (314 mg) was dissolved in 30 ml of dry methanol, to which was added about 2 g of powdered 3Å molecular sieves. The pH of this mixture was adjusted by the Addition of trifluoroacetic acid to 5, then 441 mg of sodium cyanoborohydride was added and the mixture was stirred at room temperature. After 48 hours, the mixture was filtered through diatomaceous earth, concentrated in vacuo, and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:0 then 96:4:1) to give the title compound (676 mg).

Step 3.2E 3-{2-[Benzyl-(4-pyridin-3-ylbutyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-ylamine

To a stirred solution of benzyl-{2-[2-(3,5-dimethylphenyl)-5- nitro-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl)amine (350 mg in 30 mL of absolute ethanol) was added approximately 30 mg of Raney® nickel. The reaction flask was fitted with a hydrogen balloon, evacuated and refilled with hydrogen (3 times) and stirred at room temperature. After 3 hours, the reaction was purged with nitrogen, filtered through diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) gave the title compound (246 mg).

Step 3.2F Benzyl-{2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl)amine

To a solution of 3-{2-[benzyl-(4-pyridin-3-ylbutyl)amino]ethyl}- 2-(3,5-dimethylphenyl)-1H-indol-5-ylamine (120 mg in 8 mL of dry methylene chloride) at 0 °C was added 26.6 mg of triphosgene followed by 0.050 mL of pyridine and the mixture was stirred at low temperature. After 50 min, the mixture was concentrated in vacuo to give the crude title compound (120 mg).

Step 3.2G 1-[3-{2-[Benzyl-(4-pyridin-3-ylbutyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1,4 -dihydrotetrazole-5-one

To a solution of freshly prepared aluminum azide (0.6 mmol in 6 mL of dry tetrahydrofuran) was added 120 mg of benzyl-{2-[2-(3,5-dimethylphenyl)-5-isocyanato-1H-indol-3-yl]ethyl)-(4-pyridin-3-ylbutyl)amine and the mixture was heated to reflux in an oil bath. After 20 hours, the mixture was cooled to room temperature, concentrated, poured into a mixture of 1 M sodium potassium tartrate and ice, stirred vigorously for 40 min, then partitioned between ethyl acetate and water. The organic portion was washed sequentially with 1 M sodium potassium tartrate, water and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 88:12) gave the title compound (58 mg).

Step 3.2H 1-[3-{2-[Benzyl-(4-pyridin-3-ylbutyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-4-methyl -1,4-dihydrotetrazole-5-one

To a solution of 1-[3-{2-[benzyl-(4-pyridin-3-ylbutyl)amino]-ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1,4-dihydrotetrazol-5-one (25 mg in 1.5 mL of dry N,N-dimethylformamide) at 0 °C was added 13 mg of potassium carbonate, followed by 0.033 mL of a 10% solution of iodomethane in methylene chloride, and the mixture was stirred at low temperature. After 2 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic portion was washed sequentially with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (20 mg).

Step 3.2I 1-{2-(3,5-Dimethylphenyl)-3-[2-(4-pyridin-3-yl-butylamino)ethyl]-1H-indol-5-yl}-4-methyl-1, 4-dihydrotetrazole-5-one

To a stirred solution of 1-[3-{2-benzyl-(4-pyridin-3-ylbutyl)amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-4-methyl-1,4-dihydrotetrazol-5-one (20 mg in 4 mL of methanol) was added 15 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.020 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and refilled with hydrogen (3 times) and stirred at room temperature. After 30 min, the reaction was purged with nitrogen, filtered through diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:6.5:1) gave the title compound (16 mg). m/e = 496 (M+H).

PRODUCTION OF SYNTHESIS INTERMEDIATES Step A: 4-chloro-N-methoxy-N-methylbutyramide

To a solution of 4-chlorobutyryl chloride (10.0 g in 200 ml dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride was added. The mixture was stirred under nitrogen and kept below 25 °C by cooling in an ice bath as needed while triethylamine (29.1 mL) was added dropwise over about 20 minutes, resulting in the formation of a precipitate. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate and the aqueous fractions were back extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 10.5 g (90%) of an oil which was of sufficient purity according to 1H NMR (CDCl3). Mass spectrum (PB-NH3/Cl): m/e = 166 (M + H).

Step B: 3-Chloropropyl-3,5-dimethylphenyl ketone

A solution of 10.2 mL (13.9 g, 72 mmol) of 5-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at -78 °C and 35.8 mL (84 mmol) of 2.5 M n-butyllithium in tetrahydrofuran was added dropwise. After 15 min at -78 °C, a solution of 10.0 g (60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide in 30 mL of anhydrous tetrahydrofuran was added dropwise over 25-30 min. The resulting solution was kept at -78 °C for 45 min and then warmed briefly to room temperature. The reaction was quenched by addition of 40 mL of 2 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and then saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography of the residue gave 8.91 g (70%) of an oil which was of sufficient purity according to 1H NMR (CDCl3). EXAMPLE 3.3 {2-[5-(2-Butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl)amine

Step 3.3A Benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3- yl]ethyl}carbamic acid tert-butyl ester

To a solution of benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H- indol-3-yl]ethyl}amine (EXAMPLE 3.2, Step C, 450 mg in 10 mL of tetrahydrofuran and 3 mL of water) at 0 °C was added a solution of 491 mg of di-tert-butyl dicarbonate followed by 236 mg of potassium carbonate and the resulting suspension was stirred vigorously at 0 °C. After 50 minutes, the reaction was quenched by the addition of excess saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) to give the title compound (530 mg).

Step 3.3B {2-[5-Amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}- benzylcarbamic acid tert-butyl ester

Prepared essentially as described in EXAMPLE 3.2E, starting from benzyl {2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3- yl]ethyl}carbamic acid tert-butyl ester (530 mg) to give the title compound (387 mg).

Step 3.3.C Benzyl-{2-[2-(3,5-dimethylphenyl)-5-pentanoylamino-1H- indol-3-yl]ethyl}carbamic acid tert-butyl ester

To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}benzylcarbamic acid tert-butyl ester (200 mg in 10 mL of dry methylene chloride) at 0 °C was added 0.18 mL of triethylamine, followed by the dropwise addition of 0.06 mL of valeryl chloride, and the mixture was stirred at low temperature. After 17 minutes, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed sequentially with saturated sodium bicarbonate and saturated ammonium chloride, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (230 mg).

Step 3.3D Benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester.

To a solution of benzyl-{2-[2-(3,5-dimethylphenyl)-5-pentanoylamino-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (80 mg in 3 mL of dry methylene chloride) were added sequentially 76.6 mg of triphenylphosphine, 21 mg of imidazole, 72 mg of zinc azide(pyridine complex) and 0.048 mL of diethyl azodicarboxylate and the mixture was stirred at room temperature. After 15 hours, an additional portion of zinc azide·2pyridine (29 mg) was added. After 1 hour of reaction, the pot was cooled to room temperature and the reaction mixture was applied directly to a silica gel column for purification by flash chromatography (hexane:methylene chloride:ethyl acetate, 3:4:1, then 2:0:1) to give the title compound. (57 mg).

Step 3.3E Benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}amine

To a solution of benzyl {2-[5-(2-butylpentazol-1-yl)-2-(3,5- dimethylphenyl)-1H-indol-3-yl]ethyl)carbamic acid tert-butyl ester (57 mg in 3.5 mL of methylene chloride) at 0 °C was added 0.12 mL of anisole, followed by 0.80 mL of trifluoroacetic acid, and the mixture was stirred at 0 °C. After 1.5 h, the mixture was concentrated in vacuo and the residual acid was removed by azeotropic treatment with toluene to give the crude title compound in quantitative yield.

Step 3.3F Benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl )amine

Prepared essentially as described in EXAMPLE 3.2D, starting from benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)- 1H-indol-3-yl]ethyl}amine (58 mg) to give the title compound (43 mg).

Step 3.3G {2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl)amine

Prepared essentially as described in EXAMPLE 3.2I starting from benzyl-{2-[5-(2-butylpentazol-1-yl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl)amine (43 mg) to give the title compound (34 mg). m/e = 522 (M + H). EXAMPLE 3.4 {2-[2-(3,5-Dimethylphenyl)-5-(5-isobutyl-[1,2,4]oxadiazol-3-yl)-1H-indol-3-yl]ethyl}-(4-pyridin-3-ylbutyl)amine

Step 3.4A {2-[5-Cyano-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester

Prepared essentially as described in EXAMPLE 3.3A, starting from 3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carbonitrile (prepared essentially as described in EXAMPLE 3.2, Step A) to give the title compound (300 mg).

Step 3.4B {2-[2-(3,5-Dimethylphenyl)-5-(N-hydroxycarbamimidoyl)- 1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester

A solution of {2-[5-cyano-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (300 mg in 5 mL of ethanol) was added to a suspension of 725 mg of potassium carbonate and 273 mg of hydroxylamine hydrochloride in 7 mL of ethanol and the whole was heated to reflux in an oil bath. After 21 h, the mixture was cooled to room temperature and filtered to remove solids. The filtrate was concentrated in vacuo, then partitioned between ethyl acetate and water. The organic portion was washed with water, dried over sodium sulfate and the concentrate was purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8) to give the title compound (105 mg).

Step 3.4C {2-[2-(3,5-Dimethylphenyl)-5-(5-isobutyl-[1,2,4]oxadiazol-3-yl]-1H-indol-3-yl]ethyl]carbamic acid tert- butyl ester

To a stirred solution of isovaleric acid (0.025 ml in 4 ml of methylene chloride) were added 1-hydroxybenzotriazole (37.8 mg) and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.6 mg) was added and the reagents were allowed to mix for 30 min. At this time, a solution of {2-[2-(3,5-dimethylphenyl)-5-(N-hydroxycarbamimidoyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (81 mg in 3 mL of methylene chloride) was added and the reaction stirred at room temperature. After 2 h, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to give the title compound (81 mg).

Step 3.4D 2-[2-(3,5-Dimethylphenyl)-5-(5-isobutyl-[1,2,4]oxadiazol-3-yl)-1H-indol-3-yl]ethylamine

Prepared essentially as described in EXAMPLE 3.3E, starting from {2-[2-(3,5-dimethylphenyl)-5-(5-isobutyl-[1,2,4]-oxadiazol-3-yl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (67 mg) to give the title compound (48 mg).

Step 3.4E {2-[2-(3,5-Dimethylphenyl)-5-(5-isobutyl-[1,2,4]oxadiazol-3-yl)-1H-indol-3-yl]ethyl}-( 4-pyridin-3-ylbutyl)amine

To a solution of 2-[2-(3,5-dimethylphenyl)-5-(5-isobutyl-[1,2,4]-oxadiazol-3-yl)-1H-indol-3-yl]ethylamine (22 mg in 1.5 mL of chloroform) at 0 °C was added anhydrous magnesium sulfate (38 mg) followed by 4-(3-pyridyl)butanal (11 mg) and the mixture was stirred at low temperature for 15 min. At this time, sodium borohydride (3.7 mg in 0.50 mL of methanol) was added and the mixture was stirred at 0 °C. After 30 min, the reaction was quenched by the addition of water and the mixture was extracted with ethyl acetate. The organic portion was washed sequentially with saturated potassium carbonate and brine, then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 92:8) gave the title compound (26.5 mg). m/e = 522 (M + H). EXAMPLE 3.5 (2-{2-(3,5-Dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imidazol-2-yl)ethyl]-1H-indol-3-yl}ethyl)-(4-pyridin-4-ylbutyl)amine

Step 3.5A 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5- dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester

Prepared essentially as described in EXAMPLE 3.3A, starting from ethyl 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionate (EXAMPLE 2, 1.13 g) to give the title compound (1.28 g).

Step 3.5B 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5- dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid

To a stirred solution of ethyl 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionate (1.28 g in 25 mL of ethanol) was added 30 mL of 0.5 N sodium hydroxide and the mixture was heated to 90 °C in an oil bath. After 30 h, the mixture was concentrated in vacuo, diluted with water and extracted with diethyl ether (3x). The aqueous layer was then acidified by the addition of 0.5 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.23 g).

Step 3.5C (2-{2-(3,5-Dimethylphenyl)-5-[1-(methoxymethylcarbamoyl)-1-methylethyl]-1H-indol-3-yl)ethyl)carbamic acid tert-butyl ester

To a suspension of 2-[3-(2-tert-butoxycarbonylaminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (1.23 g in 15 mL of N,N-dimethylformamide) at 0 °C were added 608 mg of 1-hydroxybenzotriazole (HOBt), 0.48 mL of 4-methylmorpholine and 352 mg of N,O-dimethylhydroxylamine hydrochloride and the mixture was stirred at low temperature. After 15 minutes, 826 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added and the mixture was warmed to room temperature. The reaction was quenched after 3.5 days by concentration in vacuo, resuspension in ethyl acetate, and washing sequentially with water, 0.3 N sodium hydrogen sulfate, water, saturated sodium hydrogen carbonate, and brine. The organic portion was dried over sodium sulfate and the concentrate was purified by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) to give the title compound (905 mg). result.

Step 3.5D {2-[5-(1,1-Dimethyl-2-oxoethyl)-2-(3,5-dimethylphenyl)- 1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester

To a solution of (2-{3,5-dimethylphenyl)-5-[1-(methoxymethylcarbamoyl)-1-methylethyl]-1H-indol-3-yl}ethyl)carbamic acid tert-butyl ester (296 mg in 5 mL of dry tetrahydrofuran) at 0 °C was added 1.8 mL of a 1 M lithium aluminum hydride solution in tetrahydrofuran and the mixture was stirred at low temperature. After 1 hour, the reaction was quenched by the careful addition of 0.3 M aqueous sodium hydrogen sulfate solution. The resulting mixture was extracted with ethyl acetate and the organic portion was washed sequentially with 0.3 M aqueous sodium hydrogen sulfate, water and brine. This was then dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 85:15) to give the title compound (253 mg).

Step 3.5E (2-{2-(3,5-Dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H- imidazol-2-yl)ethyl]-1H-indol-3-yl}ethyl)carbamic acid tert-butyl ester

To a solution of {2-[5-(1,1-dimethyl-2-oxoethyl)-2-(3,5- dimethylphenyl)-1H-indol-3-yl]ethyl}carbamic acid tert-butyl ester (475 mg in 15 mL of methanol) was added 1 mL of a 40% aqueous solution of methylglyoxal, followed by 2.2 mL of ammonium hydroxide, and the mixture was stirred at room temperature. After 2 days, an additional portion of 40% aqueous methylglyoxal (0.50 mL) and ammonium hydroxide (1.1 mL) were added. Finally, after 4 days, the reaction mixture was concentrated in vacuo, the residue redissolved in ethyl acetate and washed sequentially with water and brine. The combined organics were dried over sodium sulfate and the concentrate was purified by flash chromatography on silica gel (hexane:ethyl acetate, 1:4) to give the title compound (402 mg).

Step 3.5F 2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imidazol-2-yl)ethyl]-1H-indol-3-yl)ethylamine

Prepared essentially as described in EXAMPLE 3.3E, starting from (2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H- imidazol-2-yl)ethyl]-1H-indol-3-yl}ethyl)carbamic acid tert-butyl ester (353 mg) to give the title compound (198 mg).

Step 3.5G (2-{2-(3,5-Dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H-imadizol-2-yl)ethyl]-1H-indol-3-yl} ethyl)-(4-pyridin-4-ylbutyl)amine

Prepared essentially as described in EXAMPLE 3.2D, starting from 2-{2-(3,5-dimethylphenyl)-5-[1-methyl-1-(4-methyl-1H- imidazol-2-yl)ethyl]-1H-indol-3-yl)ethylamine (97 mg) and using 4-pyridin-4-ylbutyraldehyde to prepare the title compound (73 mg). m/e = 520 (M+1).

By following a procedure similar to that described in EXAMPLES 3.1-3.5, the following compounds were prepared: EXAMPLE 4 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(1,1-dimethyl-4-pyridin-4-ylbutylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one

Step 4A 1-(3-Methylbut-2-enyl)tetrahydrothiophenium bromide

To a solution of phenyl bromide (2.9 g in 10 mL of dry tetrahydrofuran) at 0 °C was added 1.8 mL of tetrahydrothiophene and the mixture was allowed to warm to room temperature. After 22 hours, the mixture was concentrated in vacuo and the remaining starting materials were removed by azeotroping with toluene to give the crude title compound as a white solid (2.2 g).

Step 4B 4-[3-(2-methylpropenyl)oxiranyl]pyridine

To a suspension of 1-(3-methylbut-2-enyl)tetrahydrothiophenium bromide (381 mg in 5 ml dry tetrahydrofuran) at 0ºC was added 0.31 ml pyridine-4-carboxaldehyde, followed by 111 mg sodium hydride, and The mixture was allowed to warm to room temperature. After 1.5 hours, an additional 0.15 mL of pyridine-4-carboxaldehyde was added and after 30 minutes the reaction was quenched by the addition of water. The mixture was partitioned between ethyl acetate and water and the organic portion was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 1:2) gave the title compound (138 mg).

Step 4C 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(4-hydroxy-1,1-dimethyl-4 -pyridin-4-ylbut-2-enylamino)-ethyl]-1H-indol-5-yl}-2-methylpropan-1-one

To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H- indol-5-yl]-1-(7-azabicyclo[2.2.1]hept-7-yl)-2-methylpropan-1-one (prepared essentially as described in EXAMPLE 2, 70 mg in 6 mL of dry tetrahydrofuran) was added 2 mL of a solution of 86 mg of 4-[3-(2-methylpropenyl)oxiranyl]pyridine in tetrahydrofuran, followed by 24 mg of tetrakis(triphenylphosphine)palladium, and the mixture was heated to 65 °C in an oil bath. After 2 hours, the mixture was cooled to room temperature, concentrated in vacuo. The residue was purified by flash chromatography on silica gel (methylene chloride:methanol, 92:8, then 88:12) to give the title compound (91 mg).

Step 4D 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(1,1-dimethyl-4-pyridine-4 -ylbutylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one

To a solution of 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[2-(4-hydroxy-1,1-dimethyl-4-pyridin-4-ylbut-2-enylamino)ethyl]-1H-indol-5-yl)-2-methylpropan-1-one (27 mg in a mixture of 2 mL of tetrahydrofuran and 2 mL of ethyl acetate) at 0 °C was added 0.010 mL of trifluoroacetic anhydride followed by 0.009 mL of triethylamine and the mixture was stirred at low temperature. After 15 minutes, 0.030 mL of acetic acid was added along with 28 mg of palladium hydroxide on carbon. The reaction flask was evacuated using a hydrogen balloon and refilled with hydrogen (3 times) and stirred at room temperature. After 8 hours, the reaction was purged with nitrogen, filtered through diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 94:6:1) gave the title compound (15 mg). m/e = 591 (M + H).

By following a procedure similar to that described in EXAMPLES 4 and 2, the following compounds were prepared: EXAMPLE 5.1 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[1-methyl-2-(4-pyridin-4-ylbutylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one

Step 5.1A 2-Methylcyclopropanecarboxylic acid-N-methoxy-N-methylamide

To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL of benzene and 2 mL of N,N-dimethylformamide) at 0°C was added 10.5 mL of oxalyl chloride and the mixture was stirred at 0°C for 30 min, then warmed to room temperature for 30 min. At this time 14.6 g of N,O-dimethylhydroxylamine hydrochloride was added followed by 41 mL of triethylamine. The mixture was stirred at room temperature for 1 h, then quenched by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organics were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillation under reduced pressure to give 8.9 g as an oil.

Step 5.1B (3,5-Dimethylphenyl)-(2-methylcyclopropyl)methanone

To a solution of 5-bromo-meta-xylene (5.7 mL in 120 mL of dry tetrahydrofuran) at -78 °C was added 30.6 mL of a 1.4 M solution of n-butyllithium in hexane and the mixture was stirred at low temperature. After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methylamide (5.0 g in 50 mL of tetrahydrofuran) was added dropwise over 5 minutes and the mixture was then allowed to warm slowly to room temperature. After 1 hour, the reaction was quenched by the addition of 20 mL of 2 N hydrochloric acid and 40 mL of water. This was extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate and brine, then dried over sodium sulfate to give 6.95 g of the title compound (crude).

Step 5.1C 2-[3-(2-Amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H- indol-5-yl]-2-methylpropionic acid ethyl ester

To a solution of ethyl 2-(4-hydrazinophenyl)-2-methylpropionate (5.7 g in 20 mL of n-butanol) was added 4 g of (3,5-dimethylphenyl)-(2-methylcyclopropyl)methanone, followed by 1.3 mL of conc. hydrochloric acid, and the mixture was heated to 110 °C in an oil bath. After 16 hours, the mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed sequentially with 0.5 N sodium hydroxide, water and brine. The combined organics were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (2.5 g).

Step 5.1D 2-{2-(3,5-Dimethylphenyl)-3-[1-methyl-2-(4-pyridin-4- ylbutylamino)ethyl]-1H-indol-5-yl}-2-methylpropionic acid ethyl ester

Prepared essentially as described in EXAMPLE 2, Step A, from ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1-hindol-5-yl]-2-methylpropionate (233 mg) to give the title compound (258 mg).

Step 5.1E 2-[3-{2-[Benzyloxycarbonyl-(4-pyridin-4-ylbutyl)amino]- 1-methylethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2- methylpropionic acid ethyl ester

Prepared essentially as described in EXAMPLE 2, Step B, from ethyl 2-{2-(3,5-dimethylphenyl)-3-[1-methyl-2-(4-pyridin-4-ylbutylamino)ethyl]-1H-indol-5-yl}-2-methylpropionate (258 mg) to give the title compound (240 mg).

Step 5.1F 2-[3-{2-[Benzyloxycarbonyl-(4-pyridin-4-ylbutyl)amino]- 1-methylethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2- methylpropionic acid

Prepared essentially as described in EXAMPLE 2, Step C, from ethyl 2-[3-{2-[benzyloxycarbonyl-(4-pyridin-4-ylbutyl)amino]-1-methylethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionate (240 mg) to give the title compound (222 mg).

Step 5.1G {2-[5-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H -indol-3-yl]propyl}- (4-pyridin-4-ylbutyl)carbamic acid benzyl ester

Prepared essentially as in EXAMPLE 2, Step D, described from 2-[3-{2-[benzyloxycarbonyl-(4-piridin-4-ylbutyl)amino]-1-methylethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (91 mg) to give the title compound (66 mg).

Step 5.1H 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-{2-(3,5-dimethylphenyl)-3-[1-methyl-2-(4-pyridine-4- ylbutylamino)ethyl]-1H-indol-5-yl}-2-methylpropan-1-one

Prepared essentially as described in EXAMPLE 2, Step E from {2-[5-[2-(7-Azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxoethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]propyl}-(4-pyridin-4-ylbutyl)carbamic acid benzyl ester (62 mg) to give the title compound (27 mg). m/e = 577 (M + H). EXAMPLE 5.2 1-(7-Azabicyclo[2.2.1]hept-7-yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[methyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-1H-indol-5-yl)-2-methylpropan-1-one

A dry flask containing 120 mg (0.21 mmol) of 1-(7-azabicyclo[2.2.1]-hept-7-yl)-2-[2-(3,5-dimethylphenyl)-3-[2-[4-(pyridin-4-yl)butylamino]-ethyl]-1H-indol-5-yl)-2-methylpropan-1-one (prepared essentially as described in EXAMPLE 2), 63.0 mg (2.1 mmol) of paraformaldehyde, and 200 mg of powdered 3A molecular sieves was fitted with a septum and thoroughly purged with nitrogen. Then, 5 mL of methanol and 0.121 mL (126.1 mg, 2.1 mmol) of glacial acetic acid were added and the mixture was stirred at room temperature for 15 min. Then 52.8 mg (0.84 mmol) of sodium cyanoborohydride was added, followed after another 25 minutes by 2.5 mL of anhydrous tetrahydrofuran. After 1 day, the mixture was filtered and the filter cake was washed thoroughly with methylene chloride. The filtrate was shaken with water in a separatory funnel. The aqueous phase was extracted an additional 3 times with methylene chloride. The combined organic fractions were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was concentrated to Flash chromatographed on silica gel (gradient elution with 99:1:0.1 to 95:5:0.5 CH2Cl2-MeOH-conc. NH4OH) to give 95.4 mg (79%) of a yellow stiff foam; homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-conc. NH4OH. The 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e = 577.5 (M + H).

By following a procedure similar to that described in EXAMPLES 5.1 and 5.2, the following compounds were prepared:

EXAMPLE 6

By following procedures similar to those described in EXAMPLES 1 to 5, the following compounds were prepared:

Claims (23)

1. A compound of the formula where A is C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₁-C₆ alkoxy or C₀-C₅ alkyl-S(O)nC₀-C₅ alkyl, C₀-C₅ alkyl-OC₀-C₅ alkyl, C₀-C₅ alkyl-NR₁₈-C₀-C₅ alkyl, where R₁₈ and the C₀-C₅ alkyl may be joined to form a ring, or a single bond, wherein the alkyl, alkenyl, alkoxy and alkynyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluorine, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy, R&sub0; is hydrogen, C1-C6 alkyl, aryl, aralkyl, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O (CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, R₁ is R&sub2; is hydrogen, C1 -C6 alkyl, aralkyl, aryl, alkyl-OR11 , C1 -C6 (NR&sub1;&sub1;R&sub1;&sub2;), C&sub1;-C&sub6; (CONR11 R12 ) or C(NR11 R12 )NH, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(C13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, R₂ and A together form a ring of 5-7 atoms, R₃, R₄ and R₅ are independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, CN, nitro, C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy, aryl, aralkyl, R₁₁O(CH₂)p-, R₁₁C(O)O(CH₂)p-, R₁₁OC(O)(CH₂)p-, -(CH₂)pS(O)nR₁₇, -(CH₂)pC(O)NR₁₁R₁₂ or halogen, wherein R₁₇ is hydrogen, C₁-C₆-alkyl, C₁-C₃-perfluoroalkyl or aryl, wherein the alkyl and alkenyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, R₃ and R₄ taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring with 1-3 heteroatoms, selected from N, O and S, R&sub6; is hydrogen, C1 -C6 alkyl, aryl, C1 -C3 perfluoroalkyl, CN, NO2 , halogen, R11 O(CH2 )p-, NR21 C(O)R2 0 , NR21 C(O)NR20 R21 or SOnR20, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, R�7 is hydrogen or C₁-C₆ alkyl, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, R8; is C(O)OR20, C(O)NR20R21, NR20R21, C(O)R20, NR21C(O)R20, NR21C(O)NR20R2 ;1, NR20S(O)2R21, NR21S(O)2NR20R21, OC(O)R20, OC(O)NR20R21, OR20, SOnR₂�0, S(O)nNR₂�0R₂₁, a heterocyclic ring or a bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from N, O or S, which may optionally be substituted by R₃, R₄ and R₅ or C₁-C₆alkyl, or R₇ and R₈ taken together form a heterocyclic ring having one or more heteroatoms selected from N, O or S, which may optionally be substituted by R₃, R₄ and R₅, R�9 and R9a are independently hydrogen, C₁-C₆ alkyl, aryl, aralkyl, when m ≠ 0, wherein the alkyl groups are optionally substituted by C₁-C₆alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or R�9 and R9a taken together form a carbocyclic ring of 3-7 atoms or form if m ≠ 0, R�9 and A taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, if m ≠ 0, or R₁₀ and R10a are independently hydrogen, C₁-C₆ alkyl, aryl or aralkyl, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or R₁₀ and R₁₀ taken together form a carbocyclic ring of 3-7 atoms or form, R�9 and R₁₀ taken together form a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring with one or more heteroatoms when m ≠ 0, or R�9 and R₂ taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, if m ≠ 0, or R₁₀ and R₂ taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, R₁₀ and A taken together form a heterocyclic ring having 3-7 carbon atoms and one or more heteroatoms, or R₁₁ and R₁₂ are independently hydrogen, C₁-C₆ alkyl, aryl, aralkyl or a carbocyclic ring of 3-7 atoms, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or R₁₁ and R₁₂ taken together can form an optionally substituted ring of 3-7 atoms, R&sub1;&sub3; is hydrogen, OH, NR7 R8 , NR11 SO2 (C1 -C6 alkyl), NR11 SO2 (aryl), NR11 SO2 (C1 -C3 perfluoroalkyl ), SO2 NR11 (C1 -C6 alkyl), SO2 NR11 (aryl), SO2 NR11 (C1 -C3 perfluoroalkyl), SO2 NR11 (C(O)C1 -C6 alkyl), SO2 NR11 (C(O)-aryl), S(O)n(C1 -C6 alkyl), S(O)n(aryl), C1 -C3 perfluoroalkyl, C1 - C3 perfluoroalkoxy, C1 -C6 alkoxy, COOH, halogen, NO2 or CN, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or R₁₄ and R₁₅ are independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, CN, nitro, C₁-C₃ perfluoroalkyl, C₁-C₃ perfluoroalkoxy, aryl, aralkyl, R₁₁O(CH₂)p-, R₁₁C(O)O(CH₂)p-, R₁₁OC(O)(CH₂)p-, -(CH₂)pS(O)nR₁₇, -(CH₂)pC(O)NR₁₁R₂₂ or halogen, wherein R₁₇ is is hydrogen, C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl or aryl, wherein the alkyl and alkenyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or R&sub1;&sub6; is hydrogen, C1 -C6 alkyl or N(R11 R12 ), where the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluorine, C(O)OR₁₅ ; and aryl-C₁-C₃-alkoxy, R&sub1;&sub8; is hydrogen, C1 -C6 alkyl, C(O)OR11 , C(O)NR11 R12 , C(O)R11 , S(O)nR11 , wherein the alkyl groups are optionally substituted with C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆ alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆ alkoxy, R₁₇ is either the definition of R₁₃ or that of R₁₄, R₂₀ and R₂₁ are independently hydrogen, C₁-C₆ alkyl, aryl, aralkyl, a carbocyclic ring of 3-7 atoms, a heterocyclic ring or a bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from N, O or S, which may optionally be substituted by R₃, R₄ and R₅, C₁-C₆ alkyl substituted by a heterocyclic ring or a bicyclic heterocyclic ring having 1 to 4 heteroatoms selected from N, O or S, which may optionally be substituted by R₃, R₄ and R₅, wherein the alkyl groups are optionally substituted with C₁-C₆-alkyl, C₃-C₇-cycloalkyl, aryl, aralkyl, hydroxy, oxo, nitro, cyano, C₁-C₆-alkoxy, fluoro, C(O)OR₁₅ and aryl-C₁-C₆-alkoxy, wherein the aryl groups optionally contain H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, CN, nitro, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy , aryl, C1 -C6 aralkyl, R15 O(CR13 R14 )p-, -R16 C(O)O(CR13 R14 )p -, R15 OC(O)(CR13 R14 )p-, -(CR₁₃R₁₄)pS(O)nR₁₂, (CR₁₃R₁₄)pC(O)NR₁₇R₁₈, -(CR₁₃R₁ ;₄)pNR₁₇C(O)R₁₆, -(CR₁₃R₁₄)pN(R₁₇R₁₆) or halogen, or R₂�0 and R₂₁ taken together can form an optionally substituted ring of 3-7 atoms; X is N, O, S(O)n, C(O), (CR₁₁R₁₂)p, a single bond to the radical R₈, C₂-C₆-alkenyl, C₂-C₆-alkynyl, where when X is O, S(O)n, C(O) or CR₁₁R₁₂, only R₈ is possible, Z is O, S or NR₁₁, m is 0-3, n is 0-2, p is 0-4, wherein the term aryl on each occurrence means phenyl or naphthyl, or a pharmaceutically acceptable addition salt and/or hydrate thereof, or, where applicable, a geometric or optical isomer or a racemic mixture thereof. 2. The compound according to claim 1 of the formula wherein R₁ and X-R7, R�8 are as shown in the table below: 3. The compound according to claim 1 of the formula where R₁ and XR₇, R₈ are as shown in the table below: 4. The compound according to claim 1 of the formula where R₁ and XR₇, R₈ are as shown in the table below: 5. The compound according to claim 1 of the formula where A, R₁ and XR₇, R₈ are as shown in the table below: 6. The compound according to claim 1 of the formula where R₁, R₂, R₉, R₁₀, R₁₆, R₁₀, R₁₆, XR₇R₈ and A are as shown in the table below: 7. The compound according to claim 1 of the formula where R₁, R₂, R₉, R₁₀, R₁₆, R₁₀, R₁₆, XR₇R₈ and A are as shown in the table below: 8. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor. 9. The use of a compound as defined in claim 1 for the manufacture of a medicament for antagonizing gonadotropin releasing hormone. 10. The use as defined in claim 9, wherein the gonadotropin-releasing hormone disorder is a sex hormone-related condition. 11. The use as claimed in claim 9, wherein the gonadotropin-releasing hormone disorder is a sex hormone-related cancer, benign prostatic hypertrophy or uterine fibroid. 12. The use as claimed in claim 11, wherein the sex hormone-related cancer is selected from the group consisting of prostate cancer, uterine cancer, breast cancer and gonadotropic pituitary adenomas. 13. The use as claimed in claim 10, wherein the sex hormone related condition is selected from the group consisting of endometriosis, polycystic ovarian disease, uterine fibroids and precocious puberty. 14. The use of a compound as defined in claim 1 for the manufacture of a medicament for preventing pregnancy. 15. The use of a compound as defined in claim 1 for the manufacture of a medicament for the treatment of lupus erythematosus. 16. The use of a compound as defined in claim 1 for the manufacture of a medicament for the treatment of irritable bowel syndrome. 17. The use of a compound as defined in claim 1 for the manufacture of a medicament for the treatment of premenstrual syndrome. 18. The use of a compound as defined in claim 1 for the manufacture of a medicament for the treatment of hirsutism. 19. The use of a compound that stimulates endogenous production or release of growth hormone and a compound as defined in claim 1 for the manufacture of a medicament for treating short stature or growth hormone deficiency. 20. The use of a compound as defined in claim 1 for the manufacture of a medicament for treating sleep disorders, such as sleep apnea. 21. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound which inhibits endogenous production or Release of growth hormone stimulated, in combination with a compound as defined in claim 1. 22. A pharmaceutical composition prepared by combining the compound of claim 1 and a pharmaceutically acceptable carrier therefor. 23. A process for preparing a pharmaceutical composition which comprises combining a compound according to claim 1 and a pharmaceutically acceptable carrier.